Automated Spatial Brain Normalization and Hindbrain White Matter Reference Tissue Give Improved [18F]-Florbetaben PET Quantitation in Alzheimer's Model Mice

Abstract

Preclinical PET studies of β-amyloid (Aβ) accumulation are of growing importance, but comparisons between research sites require standardized and optimized methods for quantitation. Therefore, we aimed to evaluate systematically the (1) impact of an automated algorithm for spatial brain normalization, and (2) intensity scaling methods of different reference regions for Aβ-PET in a large dataset of transgenic mice. PS2APP mice in a 6 week longitudinal setting (N = 37) and another set of PS2APP mice at a histologically assessed narrow range of Aβ burden (N = 40) were investigated by [18F]-florbetaben PET. Manual spatial normalization by three readers at different training levels was performed prior to application of an automated brain spatial normalization and inter-reader agreement was assessed by Fleiss Kappa (κ). For this method the impact of templates at different pathology stages was investigated. Four different reference regions on brain uptake normalization were used to calculate frontal cortical standardized uptake value ratios (SUVRCTX∕REF), relative to raw SUVCTX. Results were compared on the basis of longitudinal stability (Cohen's d), and in reference to gold standard histopathological quantitation (Pearson's R). Application of an automated brain spatial normalization resulted in nearly perfect agreement (all κ≥0.99) between different readers, with constant or improved correlation with histology. Templates based on inappropriate pathology stage resulted in up to 2.9% systematic bias for SUVRCTX∕REF. All SUVRCTX∕REF methods performed better than SUVCTX both with regard to longitudinal stability (d≥1.21 vs. d = 0.23) and histological gold standard agreement (R≥0.66 vs. R≥0.31). Voxel-wise analysis suggested a physiologically implausible longitudinal decrease by global mean scaling. The hindbrain white matter reference (Rmean = 0.75) was slightly superior to the brainstem (Rmean = 0.74) and the cerebellum (Rmean = 0.73). Automated brain normalization with reference region templates presents an excellent method to avoid the inter-reader variability in preclinical Aβ-PET scans. Intracerebral reference regions lacking Aβ pathology serve for precise longitudinal in vivo quantification of [18F]-florbetaben PET. Hindbrain white matter reference performed best when considering the composite of quality criteria.

Opposite microglial activation stages upon loss of PGRN or TREM 2 result in reduced cerebral glucose metabolism

“…All rodent μPET procedures followed an established standardized protocol for radiochemistry, acquisition, and post‐processing (Brendel et al , ; Overhoff et al , ). In brief, 18 F‐GE180 μPET with an emission window of 60–90 min p.i.…”

Early and Longitudinal Microglial Activation but Not Amyloid Accumulation Predicts Cognitive Outcome in PS2APP Mice

“…PET Acquisition, Reconstruction, and Postprocessing. All PET procedures followed an established standardized protocol for radiochemistry, acquisition, and postprocessing (14,20). In brief, 18 F-GE180 TSPO PET (11.2 6 1.5 MBq) with an emission window of 60-90 min after injection was used to measure cerebral TSPO expression, and 18 F-florbetaben Ab PET (10.8 6 1.5 MBq) with an emission window of 30-60 min after injection was used for assessment of fibrillary cerebral amyloidosis.…”

“…All analyses were performed by PMOD (version 3.5; PMOD Technologies). Normalization of images to SUV or SUV ratio images was performed by the previously validated myocardium correction method (21) for TSPO PET and by a white matter reference region for Ab PET (20).…”

Time Courses of Cortical Glucose Metabolism and Microglial Activity Across the Life Span of Wild-Type Mice: A PET Study

“…Accurate initial alignment was verified by a second experienced reader. In the second step, a reader-independent, fine coregistration to tracer-specific templates was performed (16). These templates had been generated by averaging all available age-specific PET scans of a single tracer after minor spatial reregistrations to ensure optimal overlapping.…”